Protective Brain Molecule May Stave Off Alzheimer's

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Scientists have long wondered why some people develop Alzheimer's
disease while others have healthy brains throughout their
lifetime. Now, new research identifies a molecule that protects
brain cells from the stress of aging, which may stave off
neurodegenerative diseases.

Researchers found that people who experience early cognitive
decline appear to have lower levels of a stress-protecting
protein in their brains compared with cognitively healthy people.
The finding suggests a possible target for diagnosing or
preventing Alzheimer's
disease and other forms of dementia.

Scientists know very little about how the human brain responds to
stress, said Dr. Bruce Yankner, a professor of genetics and
neurology at Harvard Medical School and leader of the study,
published today (March 19) in the journal Nature.

As the brain ages, cells are exposed to stress and toxins, but
some people's brains seem to be more resistant to these stresses
than others. In those with Alzheimer's disease, the leading
cause
of dementia, the brain develops characteristic sticky clumps,
or plaques, of a substance called amyloid-beta. These plaques are
clearly visible in the brain during an autopsy.

Yet puzzlingly, studies have shown that a third of people have
the brain pathology of Alzheimer's at autopsy, yet never
experienced symptoms of
cognitive decline during their lifetime. Therefore,
scientists say, something must be protecting their brains from
succumbing to the toxins.

Yankner and colleagues found that the protein known as REST
(short for "repressor element 1-silencing transcription factor")
turns off genes involved in cell death and resistance to cellular
toxins. REST, which is normally produced during
brain development, is very active in aging brains, but
appears to be missing in the brains of people with cognitive
impairment or Alzheimer's disease.

The researchers measured levels of the REST protein in the
postmortem brains of people who had taken tests of cognitive
function, and found that at death, people with higher cognitive
function had three times more of this protein in their prefrontal
cortex, the outer frontal part of the brain involved in planning,
personality and other cognitive functions.

The finding suggests that plaques and other clinical signs of
Alzheimer's may not be sufficient to cause dementia, Yankner
said, and it appears that the loss of protective proteins may
also be at work.

The REST proteins are like the police officers of the brain,
protecting it from aging stresses by turning certain genes on or
off, Yankner said. "You have a lot of crime in the brain, but
society doesn't fall apart until the police station is blown up,"
he said.

To explore the role of REST in living animals, the researchers
bred mice that lacked the REST gene, and found that these mice
were more vulnerable to aging stress and lost a significant
number of neurons in the forebrain cortex, one of the primary
brain areas affected by dementia. When the researchers restored
the REST gene to the mice, it protected the animals from
developing cognitive decline.

Yanker's team also studied the effects of stress in the roundworm
Caenorhabditis elegans. They found that worms that
lacked proteins similar to REST became more vulnerable to stress
and had shorter life spans than normal worms. This suggests the
protective function has been conserved by evolution.

Preventing cognitive decline

The researchers found that the protein isn't actually gone from
brains of people with Alzheimer's. Instead, their brain cells
continue to produce REST proteins, but cellular machinery called
autophagosomes engulf the proteins and degrade them.

The researchers are now investigating whether levels of REST
protein could be used as a diagnostic of brain health. By looking
at how much of this protein is produced in other cells of the
body, it may be possible to infer changes in the brain, the
researchers said.